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Expert Review of Anti-infective Therapy

ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20

How can we improve antibiotic prescribing in

primary care?

Oliver J. Dyar, Bojana Beovic, Vera Vlahovic-Palcevski, Theo Verheij & Céline

To cite this article: Oliver J. Dyar, Bojana Beovic, Vera Vlahovic-Palcevski, Theo Verheij & Céline
Pulcini (2016): How can we improve antibiotic prescribing in primary care?, Expert Review of Anti-
infective Therapy, DOI: 10.1586/14787210.2016.1151353
To link to this article: http://dx.doi.org/10.1586/14787210.2016.1151353

Accepted author version posted online: 06 Feb


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Download by: [RMIT University] Date: 15 February 2016, At: 11:56

Publisher: Taylor & Francis

Journal: Expert Review of Anti-infective Therapy

DOI: 10.1586/14787210.2016.1151353
How can we improve antibiotic prescribing in primary care?

Oliver J. Dyar1, Bojana Beovic2, Vera Vlahovic-Palcevski3, Theo Verheij4, Céline Pulcini5*,

on behalf of ESGAP (the ESCMID [European Society of Clinical Microbiology and

Infectious Diseases] Study Group for Antibiotic Policies)

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Global Health - Health Systems and Policy (HSP): Improving the use of medicines, Dept of

Public Health Sciences, Tomtebodavägen 18A, Karolinska Institutet, 171 77 Stockholm,

Department of Infectious Diseases, University Medical Centre Ljubljana and Faculty of

Medicine, University of Ljubljana, Japljeva ulica 2, 1525 Ljubljana, Slovenia

Department of Clinical Pharmacology, University Hospital Rijeka and Medical Faculty,

University of Rijeka, Krešimirova 42, 51000 Rijeka, Croatia

University Medical Center Utrecht. Heidelberglaan 100, Utrecht, the Netherlands
Université de Lorraine, EA 4360 APEMAC and CHU de Nancy, Hôpitaux de Brabois,

Service de maladies infectieuses et tropicales, 54511 Vandœuvre-lès-Nancy cedex, France.

Tel: + 33 (0) 3 83 15 40 97, Fax: + 33 (0) 3 83 15 35 34,

E-mail: celine.pulcini@univ-lorraine.fr

* Corresponding author

Antibiotic stewardship is a necessity given the worldwide antimicrobial resistance crisis.

Outpatient antibiotic use represents around 90% of total antibiotic use, with more than half of

these prescriptions being either unnecessary or inappropriate. Efforts to improve antibiotic

prescribing need to incorporate two complementary strategies: changing healthcare

professionals’ behaviour, and modifying the healthcare system. In this review, we present a

broad perspective on antibiotic stewardship in primary care in high and high-middle income

country settings, focussing on studies published in the last five years. We present the limitations

of available literature, discuss perspectives, and provide suggestions for where future work
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should be concentrated.

Keywords: antibiotic stewardship, general practice, nurse, pharmacist, intervention

1. Background

Rising rates of antibiotic resistance, in combination with a lack of new effective

antimicrobials, is leading to increased morbidity, mortality and healthcare costs [1]. Antibiotic

use is the main driver for the development and spread of antibiotic resistance, and the vast

majority of antibiotic use currently occurs in outpatient settings. Ambulatory antibiotic

consumption accounted for between 85 to 95% of total antibiotic use in 2012 in the European

Union, according to countries contributing data on both ambulatory and intra-hospital antibiotic

use to the European Centre for Disease Prevention and Control (ECDC) [2]. The main

prescribers of antibiotics in primary care settings are general practitioners (GPs), paediatricians
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and dentists, but in many countries a growing number of prescriptions are written by nurses,

midwives and pharmacists, typically for specific patient groups or infections [3].

Several studies show that antibiotic prescribing in outpatients is frequently unnecessary

or inappropriate. For both adults and children, misuse has been most often reported in acute

respiratory infections, which usually represent two-thirds of all infections with which patients

are seen in primary care [4,5]. The rate of unnecessary prescribing for respiratory infections

(RTIs) for which antibiotics are rarely indicated ranges from one half to 90% [4-7]. Less is

known about inappropriate or unnecessary prescribing for other types of infections. French

authors recently reported that only 20% of prescriptions for urinary tract infections (UTIs) were

compliant with guidelines [8]. For skin infections, authors from Colorado (USA) reported that

46% of antibiotic prescriptions were unnecessary [9].

It is difficult to compare outpatient antibiotic use worldwide due to the heterogeneous

methodologies used to collect and aggregate data. Nevertheless, it is clear that there are large

variations in outpatient antibiotic prescribing in European countries. In 2013, there was a 3-

fold difference between the countries with the highest and the lowest consumption [2]. The
outpatient antibiotic use in the USA, measured in prescriptions per 1000 inhabitants per year,

is comparable to the highest consumers in Europe [10]. There are even greater variations in

antibiotic prescribing between prescribers in the same country, and this is a strong rationale for

efforts to improve behaviours at the level of the individual [11].

A landmark Cochrane systematic review in 2005 assessed interventions aiming at

improving antibiotic prescribing practices in ambulatory care [12]. Since then, a few narrative

and systematic reviews have focussed on different aspects of antibiotic stewardship in the

outpatient setting [13-18], the most recent of which included articles published up until

November 2013 [18].

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In this narrative review, we will describe the global context of antibiotic prescribing in

primary care (excluding long-term healthcare facilities), as well as interventions designed to

improve antibiotic use. We will do this from a purposefully broader perspective than previously

published reviews. In order to present the latest evidence and developments, we mostly discuss

articles published between 2010 and 2015. Our target audience are practitioners and researchers

in primary care settings in high and high-middle income country settings; for this reason, our

review is restricted to articles relevant to this context. We do recognise the global need for

collating evidence relevant to less developed settings, and we acknowledge that such data is

currently scarce and difficult to evaluate.

2. General principles of antibiotic stewardship programmes in primary care

Efforts to improve antibiotic prescriptions may be single interventions or packaged as

part of a more general programme, and may be implemented locally and/or nationally. In many

countries we cannot yet speak about nationwide antibiotic stewardship programmes, but merely

more or less coordinated activities. The countries with the lowest outpatient antibiotic use, such

as the Netherlands and Sweden, have implemented actions to promote prudent

antibiotic use in primary care for a long time. At the same time, these countries now have the

lowest rates of antimicrobial resistance in Europe. In the Netherlands, there is a strong

collaboration among professional societies, and a distinct nationwide antibiotic stewardship

programme for primary care is planned for the coming year. Antibiotic prescribing guidelines

are widely used, and prescription habits are monitored in general in primary care, but not for

antibiotics in particular. Strong medical education efforts also underlie the prudent use of

antibiotics. The Swedish model, known as the Strama network, relies on multi-sectorial

collaboration at local and national levels: comprehensive regional antibiotic stewardship

programmes targeting primary care prescribers are in place, combining different interventions,
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and involving a network of healthcare professionals. A similar system is also implemented in

some regions in France [17].

The interventions that are most successful at reducing inappropriate antibiotic

prescribing tend to be multifaceted, and combine physician, patient and public education [12].

Importantly, we are now starting to see a growing number of reports from ‘real world

implementations’ of such multifaceted packages of interventions, with promising

improvements in antibiotic usage across large populations [19]. In a recent systematic review

focussing on RTIs, 77% of 87 interventions contained more than one element, most commonly

educational meetings, printed materials for prescribers, and audit/feedback [15].

The authors in the 2005 Cochrane review concluded that the effectiveness of

interventions depended largely on prescribing behaviour and on the barriers to change [12].

This indicates that the design of interventions should be based on behavioural strategies [20].

The local cultural context also has an important influence on physicians and patients’

behaviours. Hofstede's model of cultural dimensions, one of the most popular models assessing

cultural differences, has been used to explore the differences in outpatient antibiotic use in

European countries. A positive correlation was found between power distance index,
which is a marker of a hierarchical society, and outpatient antibiotic consumption, including

self-medication. Antibiotics were also used more frequently in countries with high index of

uncertainty avoidance, i.e. countries in which people and organisations have a low tolerance for

uncertainty [21]. This signifies the importance of implementing antimicrobial stewardship

interventions both at the provider-level and at the level of the healthcare system.

3. Practical measures to improve antibiotic use in primary care (Table 1)

3.1. Provider-level interventions

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3.1.1. Education (including academic detailing and training in communication skills)

Postgraduate education in antibiotic stewardship is frequently included as part of a

broader package of continuing medical education for prescribers. Educational sessions can

involve training in core principles of prudent antibiotic usage, introductions to new supporting

tools (such as guidelines and point of care tests), and training in communication with patients.

Several recent major studies have shown positive outcomes on antibiotic prescribing in

response to educational interventions, although the sizes of the effects have generally been quite

modest [22-26]. The STAR programme in the UK developed internet-based resources and in-

person training, as well as practice-specific feedback, and led to a 4.2% reduction in the adjusted

oral antibiotic prescribing rate compared with control practices [22]. Respondents in a

qualitative assessment of the programme reported that the most effective components were the

up to date research evidence, the training in communication skills, and the feedback on their

own practice’s antibiotic dispensing rates and resistance patterns [23]. The GRACE- INTRO

study included one intervention arm that received internet-based communication skills training,

in conjunction with an interactive patient booklet. It was delivered in 246

primary care practices across six European countries, and led to an average 9% reduction in

antibiotic prescribing rates for RTIs [24]. Qualitative and quantitative analyses of participating

GPs and patients showed high levels of satisfaction with the communication skills intervention,

with GPs perceiving reducing antibiotic prescribing as more important and less risky after the

online training session [25,26].

Importantly, a small number of studies have recently shown that educational sessions

on a variety of topics (guidelines, diagnostic skills, communication skills) can lead to

improvements in antibiotic usage that are sustained over two to four years [27,28], and even in

response to single seminars [29]. We now have examples of educational interventions that are
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both low-cost and easily scalable, as well as interventions that have long-term effects on


3.1.2. Guidelines and clinical decision support systems

Guidelines are an important way to support prescribers in translating the best evidence

into clinical practice. Many countries have issued national guidelines to help improve antibiotic

prescribing in both inpatient and outpatient care, however there have been very few recent

assessments of the effects of national guidelines on prescribing behaviour. Three studies in the

USA found that publication of national guidelines had minimal or no impact on rates of

antibiotic prescriptions for acute otitis media, otitis externa or sinusitis, although there were

some improvements in antibiotic selection [30-32]. Stronger evidence exists for the

implementation of guidelines at a regional or local level [33]. One study conducted at two out

of hours primary care centres in Belgium provides insight into the local implementation and

clinical adoption of a guideline for treatment of UTIs [34]: in addition to the distribution of

posters and information leaflets at the centre, individual prescribers were emailed a copy of the

guideline before starting clinical sessions with patients. This led to a significant rise in the
proportion of UTIs treated with guideline appropriate antibiotics; however, a follow-up review

after a 17 month washout period found that guideline adherence had returned to near baseline


Clinical decision support tools and systems (CDSS) have become more prevalent over

the past decade, particularly in primary care settings where electronic health records and e-

prescribing are common. A recent systematic review examined the effects of CDSS on

antibiotic prescribing in primary care, identifying seven studies which all focussed on RTIs and

were all conducted in the USA: there was great variation in the rates of triggering of the CDSS

(2.8% to 62.8% of eligible encounters), and five of the studies reported a slight to moderate
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effect on improving antibiotic prescribing behaviour [35]. These improvements were mostly

associated with increased selection of recommended antibiotics, but not reductions in rates of

antibiotic prescribing. In the UK, a CDSS was integrated into the electronic health record

system at 53 primary care practices to encourage delayed or no prescribing of antibiotics for

patients with RTIs as part of the eCRT study [36]. Compared with 51 control practices, there

was a slight reduction in the rate of consultations involving an antibiotic prescription (1.9%),

and a larger reduction in the rate of antibiotic prescription for RTIs (9.7%). GPs in the

intervention group were satisfied with the CDSS and reported higher levels of self-efficacy in

managing patients with RTIs according to recommended guidelines; actual usage of the CDSS,

however, was highly variable and was lower than expected by the investigators [36,37].

3.1.3. Delayed prescribing

Delayed prescribing describes a situation in which a clinician reviews a patient and

prescibes a course of antibiotics, but specifies that they should only be taken if symptoms persist

or deteriorate after a given time period (typically around 48 hours). Depending on how
prescriptions are handled within the particular health system, the patient may either be unable

to collect the prescription or unable to have the antibiotics dispensed before this time period has

elapsed; in other settings, they may be able to collect antibiotics on the same day that they

visited the clinician, but are simply advised to delay starting taking the antibiotics. These health

system differences may impact on the value of delayed prescribing for a particular setting.

Spurling et al. recently conducted a systematic review on the use of delayed

prescriptions for acute RTIs [38]. They reported that the use of delayed prescriptions led to

reductions in the use of antibiotics, with no important differences in reconsultation and

complication rates. Overall patient satisfaction was slightly lower for delayed antibiotics than
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for immediate antibiotics, and was similar to not receiving antibiotics.

In an observational study of patients with sore throat in the UK, Little et al. found a low

overall rate of complications for delayed prescribing (1.4%, mostly otitis media, sinusitis) [39].

Importantly, delayed antibiotics were as effective as immediate antibiotics at preventing

complications compared with no antibiotics, and were more effective than immediate

antibiotics at reducing reconsultations. In another study in patients with all types of acute RTIs

in the UK, different strategies for delayed prescription were compared with either no antibiotics

or immediate antibiotics [40]. Symptom severity, duration of symptoms, and patient satisfaction

were similar across all groups, but delayed prescription and no antibiotics resulted in lower

antibiotic use and lower levels of patient belief in the need for antibiotics, compared with

immediate antibiotics.

Delayed prescribing is now recommended in some national guidelines, such as the UK.

Despite this, observational studies have reported low usage of delayed prescriptions in practice

[41,42]. A qualitative study with GPs in the UK suggested that they mostly use delayed

prescribing as a way to manage diagnostic uncertainty and to avoid conflict with

patient expectations. However, some prescribers feel uncomfortable giving clinical

responsibility to patients, and the use of delayed prescribing was felt to communicate

conflicting messages to patients about the general efficacy of antibiotics for respiratory tract

infections [42]. Mixed opinions were also found among Norwegian GPs, with some viewing it

is as an opportunity to educate patients and engage in shared decision making; in contrast, those

who were more negative towards delayed prescribing viewed it mainly as a tool to use for

patients who were putting them under pressure to prescribe antibiotics [43]. Interestingly, 89%

of patients who received a delayed prescription in the same Norwegian study said they would

prefer to receive a delayed prescription again in the future [44].

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3.1.4. Patient materials: dedicated forms to prescribe antibiotics, non-prescription pads and

patient information leaflets

To the best of our knowledge, antibiotic prescriptions in primary care are almost never

individualized on a specific prescription form given to the patient [17]; the patient usually

receives a prescription with all the drugs put together. The idea of using a dedicated form on

which only antibiotics are prescribed is currently being discussed in France, since it has several

theoretical advantages: highlighting that antibiotics are special drugs, being a tool facilitating

the patient-doctor relationship (since educational messages can be added to the form), and

ultimately decreasing antibiotic use. It would also enable patients to easily identify the

antibiotics among the drugs they are prescribed.

Non-prescription pads are currently used in several countries [17], including the UK.

The pad looks like a normal prescription pad and includes ‘non-prescription’ forms that can be

given to patients who present with an infection, but who do not need a prescription for

antibiotics. The forms provide physicians with an aid to explain why antibiotics are not part of

treatment for a particular condition, and may also include descriptions of the usual duration of
symptoms, such as cough or fatigue, and suggestions of symptomatic therapies [13]. This

educational and communication tool can be tailored to a specific clinical situation, facilitates

the patient-doctor relationship, and can replace a drug prescription in countries where patients

expect some kind of prescription from their doctors.

Patient information leaflets have also become increasingly popular in primary care over

the past decade. These can be used as a reference by clinicians during consultations, and patients

are able to take them away to review later. The EQUIP study in the UK showed that antibiotic

prescribing rates for children with RTIs could be reduced with the help of a patient information

booklet [45]. An in depth qualitative follow-up with GPs and parents concluded that the booklet
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was easy to use, with parents valuing most the information on recognising signs of serious

illness and on the usual duration of illness [46]. Although many GPs reported increased

knowledge and confidence as a result of using the booklet, some also mentioned important

barriers to use, such as a lack of time and difficulty in modifying their style of consultation.

Several recent studies have included patient information leaflets as part of a broader set of

interventions [47-49]. The GRACE-INTRO study included provision of an information booklet

in conjunction with training in communication [26]. Almost all patients who received the

booklet recounted using it, and these patients later reported the highest levels of satisfaction and

enablement across all the study intervention groups (which included a point of care testing arm),

as well as the greatest awareness that antibiotics could be unnecessary.

3.1.5. Public commitment

A recent American study showed that displaying poster-sized commitment letters in

consulting rooms decreased inappropriate antibiotic prescribing for RTIs (20% absolute

percentage reduction) [50]. In the letter, the individual clinicians stated personal commitments
to avoiding inappropriate antibiotic prescribing for acute respiratory infections. The efficacy of

this innovative strategy likely relies on the psychological tendency for people to prefer to act in

ways that are consistent with their previous commitments, particularly when these are public.

This strategy is currently implemented nationwide in hospitals in France, with the support of

the French Infectious Diseases society, and will probably be rolled out in all settings in France

in the near future.

3.1.6. Point of care (POC) diagnostic tests

Rapid antigen diagnostic tests (RADTs) have long been recommended in some countries
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to identify the presence of group A streptococcal pharyngitis; however, their use is quite

context-dependent. In a pragmatic parallel group randomised control trial in the UK, Little et

al. found that using a clinical score for patients with a sore throat reduced antibiotic usage

compared with a strategy of delayed prescribing, but that there was no additional benefit from

also using a rapid antigen test in conjunction with the clinical score [51]. In France, RADTs are

freely available to GPs, but they are largely underused [52].

Two meta-analyses have been published on the effects of POC CRP testing on reducing

antibiotic use in patients with upper or lower respiratory tract infections in primary care [53,54].

Both analyses concluded that CRP testing reduces the rate of antibiotic prescriptions at the

index consultation without leading to increased rates of re-consultation or worsened clinical

recovery; however, there was a high level of heterogeneity among the individual studies

included. A recent narrative review by Cooke et al. reports that GPs and patients find the CRP

POC test acceptable, and that its use is economically justifiable in high- income country settings

[55]. The authors caution, though, that it remains unclear to what extent CRP testing can

distinguish between viral and bacterial infections; indeed most studies show that CRP testing

in isolation cannot adequately make this distinction.

3.1.7. Selective susceptibility reporting

Antibiotic susceptibility data reporting strongly influences physicians’ prescribing

behaviour, and selective reporting is a powerful antibiotic stewardship tool that is probably

underused. Studies conducted among GPs have demonstrated that the antibiotics reported by

the microbiology laboratory are preferentially prescribed [56]. Moreover, a randomised case-

vignette study conducted among French doctors training in general practice showed that

selective reporting improved the appropriateness of antibiotic prescriptions for urinary tract

infections compared with full-length reporting of antibiotic susceptibility data [8].

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3.1.8. Quality indicators

Disease-specific indicators have been developed in Europe to assess the quality of

antibiotic use in primary care, and are currently used for national reporting [57]. As part of the

HAPPY AUDIT project, a group of international experts reached consensus through a modified

Delphi method on 41 quality indicators for the diagnosis and treatment of respiratory tract

infections in primary care [58]. Out of these indicators, 14 were on the decision to start antibiotic

treatment (e.g. proportion of patients with lower RTI and CRP <20 mg/L who are treated with

antibiotics) and 27 were on the choice of antibiotic (e.g. proportion of patients with acute

sinusitis treated with a narrow-spectrum penicillin, or with macrolides). Indicators focussing on

the diagnostic process had been proposed initially, but none were included in the final selection

due to a lack of agreement. In a follow-up study, 58 Danish GPs were asked if they agreed on

the 41 indicators; none of the indicators were agreed on by all of the GPs, and only 33 of the 58

GPs agreed on more than 50% of the indicators [59]. Almost all indicators published in the

literature need data on clinical diagnoses, even though some countries (such as France and

Slovenia) do not have routine access to these data.

Quality indicators based on reimbursement data have been published, and could be useful in

this case [11,60,61]. An Innovative Medicines Initiative (IMI)-funded European project is

currently working on a consensual inventory of quality indicators assessing antibiotic use in the

outpatient setting (DRIVE-AB project).

3.1.9. Audit and feedback

The increasing use of electronic health records in primary care settings has facilitated

data capture of prescriptions and the ease with which such data can be converted into feedback

for prescribers. Many recent studies have included some aspect of prescription feedback as part
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of a package of interventions, providing data either at the level of the individual or primary care

practice. Hurlimann et al. found that twice-yearly individual feedback on antibiotic

prescriptions was sufficient to cause improvements in guideline adherence across 140 Swiss

primary care practices in the context of newly developed guidelines for both respiratory tract

infections and urinary tract infections [62]. Individual feedback was provided to prescribers in

24 primary care practices in the USA in a study focussing on improving adherence to otitis

media management guidelines [63]. This monthly feedback had a stronger effect on

improvements in care than a clinical decision support tool that was trialled at the same time.

Studies by Gerber et al. in paediatric primary care practices in the USA have highlighted the

importance of continuing audit and feedback in order to sustain improvements in the longer

term: initially, reductions were seen in the use of non- guideline broad-spectrum antibiotics for

RTIs at 9 intervention practices after an educational seminar and quarterly individualised

prescription feedback [64]. A follow-up study after 18 months without audit and feedback then

showed that broad-spectrum antibiotic use had returned to baseline levels in the intervention

practices [65].
3.1.10. Restrictive antibiotic prescribing measures

This topic has been recently reviewed [17]. Implementing restrictive measures in the

outpatient setting is not easy, and few countries have done so. As examples, in Slovenia,

primary care prescribers pay a fine if certain antibiotic prescriptions do not comply with existing

national guidelines (e.g. prescriptions that inappropriately include amoxicillin- clavulanic acid,

fluoroquinolones, macrolides, third-generation cephalosporins). The Slovene Health Insurance

Institute is auditing medical records in order to enforce this policy [66]. In Turkey, specific

antibiotics cannot be prescribed without approval from an infectious diseases specialist. In the

Netherlands, insurance companies look at prescription rates and types of antibiotics; when the
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use of second-choice agents is above a certain limit (based on national/regional averages), this

can have financial consequences for the primary care practice involved in the form of reduced


3.2. Healthcare system-level interventions

Prescribers and primary care practices are subjected to a number of rules and regulations

that may have an impact on their antibiotic prescribing behaviour [67]. Quite surprisingly, this

topic has not been extensively studied so far, even though changing these systems might have

quite a large, widespread and sustainable impact on antibiotic consumption. The interventions

we describe in this section are more complex than interventions at the level of the provider; for

instance, they may require a far broader group of stakeholders to be involved in decision-

making, and their implementation may take a comparatively longer time. This may partly

explains the limited number of published assessments of their effectiveness so far. The recent

World Health Assembly commitment that many countries have made to developing national

action plans for combating antibiotic resistance may help stimulate research efforts into health

system-level interventions.
3.2.1. Over-the-counter antibiotics

In many countries, antibiotics are available without any prescription (i.e. over-the-

counter), from pharmacies, the Internet, family, friends or at home [67-69]; it is estimated that

19–100% of antimicrobial use outside of northern Europe and North America is non-

prescription based [68]. When this practice is legally prohibited and the laws are appropriately

enforced, antibiotic use is reduced [68-70]. There are several countries in which non-

prescription use is now illegal, but in which the practice remains widespread (for example,

Spain and Greece) [71]. As a general rule, antibiotics should not be available without a
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prescription, and a regulated list of authorised and adequately trained antibiotic prescribers

should exist in all countries.

3.2.2. Unit dispensing

Unit dispensing of antibiotics (i.e. the pharmacist gives the exact number of antibiotic

pills to the patient, according to the prescription) has been associated with a lower risk of future

self-medication with leftover antibiotics [72]. This measure is already in place in some countries

(such as the UK, the Netherlands and the USA), and is under evaluation in others (for example,


3.2.3. Number of antibiotics available and antibiotics’ price

Limiting the number of antibiotics available in the outpatient setting, or increasing their

price, might reduce antibiotic use [67]. Monnet et al. found that the more oral antibacterial trade

names (whether generic or branded versions) that are on the market, the higher the outpatient

consumption of antibacterial agents [73]. This was confirmed in a more

recent European study [74]; however, no causal relationship can be inferred from these


The relationship between the price of antibiotics and antibiotic use is complex, and

depends on the healthcare system regulation. In countries where patients pay partly or totally

for their own medicine, it is likely that when prices go down, products become affordable for a

larger proportion of the population, which leads to increased consumption; this association was

indeed demonstrated in European countries [75]. In Turkey, an increase in fluoroquinolone use

was seen after a reimbursement reform was introduced, making fluoroquinolones less expensive

[76]. Conversely, a reduction in reimbursement for antibiotics can lead to decreased use [69,77].
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Two studies, conducted in Denmark and in Germany, have also shown that generics can

lead to increased antibiotic use, either by increasing the number of marketed versions of the

drug and/or by decreasing the price of the antibiotic [77,78]. Interestingly, the incentives were

different in both countries: Danish patients receive a relatively low reimbursement for

outpatient medication, whereas German ambulatory care physicians are generally self-

employed, and the national health insurance reimburses fixed budgets for pharmaceuticals.

3.2.4. Prescribing and dispensing of antibiotics

Prescribing should be separated from dispensing of antibiotics [67], since there is a clear

motivation to increase prescribing in situations when prescribers can sell or dispense antibiotics

for profit, such as China and Switzerland. In these countries dispensing physicians can increase

their revenues by inducing drug consumption [67]. “Zero-markup” schemes specifically for

antibiotics may weaken the economic incentive, and are now being implemented in China;

unfortunately, many healthcare institutions have become heavily reliant on profits from

antibiotic sales, which means this intervention will create a need to

profit from other activities instead. Prescribing and dispensing has been separated in some

countries in recent times, such as Taiwan and South Korea, and has led to reduced drug

expenditure [69].

3.2.5. Prescribers’ remuneration system

In primary care, healthcare professionals can be paid in different ways: fee-for-service,

capitation or salary. These systems can have a great influence on prescribing practices [67], and

it has been shown in a European study that a capitation system is associated with decreased

antibiotic use [75]. An interventional study conducted in China further showed that
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implementing capitation with pay-for-performance systems led to a significant decrease in

antibiotic use [79].

3.2.6. Pay-for-performance

Pay-for-performance systems are used in many countries, meaning that financial

incentives are given to prescribers when they meet specific quality of care targets, including

quality indicators for antibiotic prescriptions [17,67,80]. The efficacy of pay-for-performance

systems is debated, however, and should be carefully assessed in each specific context [81].

3.2.7. Public reporting of healthcare performance

In recent decades, public reporting of healthcare performance (data disclosed to patients

and healthcare professionals) has been used as an instrument to improve the quality of care

[67]. Existing evidence shows this has mixed effects, and may be useful in certain settings [82].

As an example, an interventional study conducted in China showed a significant decrease in

antibiotic use after implementation of public reporting [83].

3.2.8. Sickness leave regulation

Visiting a doctor for a self-limiting infection increases the chances of being prescribed

an antibiotic. In some countries, such as the Netherlands, primary care providers are not

responsible for issuing sick certificates. Instead, sickness certification is carried out by fully

independent dedicated doctors and nurses, who are not involved in actual diagnosis and

treatment of patients. In other countries, such as France and Slovenia, a certificate is arranged

by the patient’s GP and is usually needed as soon as possible. Such differences might be

contributing to the existing variations in outpatient antibiotic use seen across countries.
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3.2.9. Pharmaceutical advertising

Direct-to-consumer advertising of antibiotics and unregulated access of pharmaceutical

representatives to prescribers are risk factors for increased antibiotic use [14,67,74]. In their

European-wide cross-sectional study, Blommaert et al. found that the presence of restrictions

on the conduct of pharmaceutical companies towards physicians was associated with less

antibiotic use at the country level [74]. Many countries are now implementing restrictions on

these practices.

4. The roles of pharmacists and nurses

Hospital pharmacists are key actors in antimicrobial stewardship teams in hospitals; in

the community, pharmacists are ideally positioned as frontline healthcare providers to promote

prudent antibiotic use. Similarly, there is a growing understanding of the potential roles that

nurses may be able to take on within antibiotic stewardship programmes, both inside and

outside of hospitals. Whilst it is clear that nurses and pharmacists should be able to
contribute to antimicrobial stewardship in primary care in many ways, a detailed assessment

of these roles is limited by the paucity of recent studies.

4.1. Pharmacists’ roles

Community pharmacists provide convenient access to a qualified healthcare

professional without an appointment. Pharmacists routinely advise on minor ailments such as

UTIs and sore throats, and play an important role in patient education, particularly in explaining

when antibiotics are useful and how antibiotics should be taken. In the UK, patient access to

care improved through community pharmacies supplying trimethoprim under specific

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instructions for uncomplicated UTIs [84]. Recently, pilot projects have been launched in 3 states

in the USA, stimulating collaboration between physicians and community pharmacists to treat

patients with influenza and group A streptococcal pharyngitis. Under this model, community

pharmacists are entitled to use RADTs to guide clinical decision-making and to initiate

treatment under a physician-led, evidence-based protocol [85]. These initiatives show how

strong collaboration between physicians and pharmacists in the outpatient setting can help

contribute to efficient antibiotic stewardship programmes.

4.2. Nurses

With appropriate training, nurses can contribute to educating patients on the prudent and

appropriate use of antibiotics, as well as non-antibiotic treatment options for minor, self-

limiting infectious diseases. This is particularly important as task-shifting is increasingly

embraced in efforts to reduce costs in primary care, with many patients now undergoing first

assessment by nurses in some countries. Despite this, we failed to identify any published studies

focussing on the role of nurses specifically within antibiotic stewardship programmes in

primary care.
One recent study analysed patterns of antibiotic prescribing by nurses working in

primary care in Scotland over the 2007-2013 period [86]. On average, antibiotics were present

on one in every five prescriptions written by nurse prescribers. Appropriateness of antibiotics

prescribed was not assessed in detail in this study, but the results showed improving trends in

the prescription of first-line antibiotics and improvements in prescribing quality indicators

during the observed period of time (reduction in the proportion of broader-spectrum agents,

more frequent appropriate duration of treatment of adult females with urinary tract infection

and increased use of recommended doses).

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5. Conclusions

The threat of antimicrobial resistance, an inevitable consequence of antibiotic use, urges

us to engage in prudent antibiotic prescribing. Outpatient antibiotic use represents 85 to 95% of

total antibiotic use. The majority of antibiotics in outpatients are prescribed for respiratory tract

infections. Several studies have shown that antibiotic prescriptions are either unnecessary or

inappropriate in more than one half of cases.

Education is central to preparing healthcare professionals for the challenges of antibiotic

stewardship in primary care, and to keeping them updated throughout their careers. At the

undergraduate level, curricula and teaching should be strengthened, particularly since a large

proportion of graduates of medical, nursing and pharmacy courses will later work in primary

care [3]. However, education alone will be insufficient to deliver the broad improvements that

are now urgently needed. Improving antibiotic prescribing relies on two complementary

strategies: changing healthcare professionals’ behaviour, which is often not easy to achieve, and

modifying the healthcare system. Given the breadth of potential methods and targets for

improvement, it is perhaps not surprising that multifaceted interventions have proved useful in

improving antibiotic prescribing. We must keep in mind the concept of ‘One

size does not fit all’ as well as that of ‘No magic bullet’: the implementation of evidence- based

interventions from one setting in another is greatly strengthened by taking time to tailor them

to the relevant socio-cultural context, which influences prescribers’, patients’ and even

healthcare systems’ attitudes to antibiotics.

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Expert commentary

Most antibiotic stewardship efforts have focussed on hospitals so far, even though 90%

of antibiotics are prescribed in primary care. It is time to make antibiotic stewardship in primary

care a priority.

The majority of studies we have found targeted healthcare professionals working in

Europe or North America, and included interventions aimed only at GPs. Almost all studies

focussed exclusively on respiratory tract infections. Many studies confirm that it is easier to

influence selection of antibiotic (i.e. substitution for inappropriate prescriptions) than it is to

reduce rates of antibiotic prescribing (i.e. limiting unnecessary treatments). It is very clear that
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we must find effective ways to reach this second target. Information on durations of treatment

was almost never reported in studies, even though shortening treatments’ duration is probably

a low-hanging fruit. In practice, many interventions (guidelines, CDSS, POC tests, delayed

prescribing) had low usage rates compared with potentially eligible encounters, possibly

because barriers to use were not assessed and addressed beforehand. Data regarding

sustainability and scalability of interventions were limited, as found by Drekonja et al. in their

recent systematic review [18]. Assessment of impact of any intervention on resistance rates was

absent. Finally, publication bias is also likely, since negative findings were rarely reported.

We recommend that all healthcare professionals (e.g. all physicians working in primary

care, nurses, pharmacists, midwives, dentists, microbiologists…) are involved in future

projects. A global approach is needed as we use in hospitals, taking into account the contextual

and cultural specificities as well as the complex interactions between healthcare professionals,

their patients and the healthcare system. Solid methodologies are also needed [87], with data on

sustainability of the impact of interventions, as well as on feasibility and applicability in daily

practice. The recent study by van der Velden et al. in the Netherlands
provides a good example of a pragmatic multifaceted intervention embedded into many aspects

of a primary care practice: this combined prescriber education, audit/feedback and patient

leaflets, with accreditation of primary care practices [7]. The model used in Sweden may be a

source of inspiration for other countries. It consists of regional organisations that are capable

of: a) driving and innovating behavioural change at the individual/local level, and b) pooling

sufficient resources and engagement to change some healthcare systems.

We must also ‘think outside the box’, and test innovative strategies, including changes

in the organisation of the healthcare system. For example, few studies have used simulated

patients (i.e. individuals trained to act as a real patient in order to simulate a set of symptoms
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or problems, and who could be used to assess care and compliance with relevant standards in a

blinded way) or quality circles (meetings with peers/pharmacists to discuss practices, using

quality improvement strategies) [88]. Most interventions published so far have focussed on the

prescriber, but changing the system is sometimes a more powerful tool.

Five-year view

We sincerely hope that antimicrobial stewardship will soon become a strong

international political priority, given the worldwide crisis on antimicrobial resistance. Political

commitment is a pre-requisite if innovative and courageous organisational changes and

restrictive measures are to be implemented. The WHO Global Action Plan adopted at the World

Health Assembly in 2015 requires all countries to develop national action plans, and is likely

to stimulate the development of more regional and national antibiotic stewardship programmes

in the coming years.

Information technologies will be increasingly used to support prescribers in their

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decision-making and to automate monitoring of key indicators, with regular feedback and

benchmarking. Enhanced access to such data for research will allow more studies to look at

population-level improvements in antibiotic prescribing, whilst also permitting resolution to the

level of individual prescribers.

Non-clinical professionals, such as psychologists, sociologists, health economists, and

communication specialists, will be more frequently involved in order to design innovative and

comprehensive strategies. Multidisciplinary networks with strong and visible professional

engagement will develop, and the general public will be included in these initiatives. We will

also have a better idea of the types of multifaceted interventions that can lead to scalable,

sustainable real-world improvements in antibiotic use, across a far broader range of settings.
Key issues

 Around 90% of antibiotics used in human medicine are prescribed in primary care. At

least half of these prescriptions are either unnecessary of inappropriate.

 Multifaceted interventions have proved useful in improving antibiotic prescribing, but

they should be adapted to the context (‘One size does not fit all’ and ‘No magic bullet’

concepts). Behaviour change theories are helpful for designing interventions that target

healthcare professionals.

 Recent evidence related to various interventions targeting healthcare professionals are

described here (Table 1): education, guidelines, clinical decision support systems,
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delayed prescribing, patient materials, public commitment, point of care diagnostic

tests, selective susceptibility reporting, quality indicators, audit and feedback and

restrictive prescribing measures.

 Interventions targeting the healthcare system have been overlooked so far, even though

their impact can be large and sustained. Some examples are given here, including:

dispensing of antibiotics, financial incentives and public reporting.

 Most published studies come from Europe or North America. We need studies from a

much greater range of settings.

 Most interventions have focussed on general practitioners. In the future, all healthcare

professionals should be targeted. Most studies have focussed on respiratory tract

infections; we need to develop a better understanding of how much improvement is

possible for other conditions, and how well suited our current interventions are to

achieving this.

 Patient-centred outcomes remain largely under-developed and under-reported.

 Innovative strategies, including those targeting the system organisation, should be

Financial and competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Reference annotations

* Of interest

** Of considerable interest

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Table 1: Summary of the interventions discussed in this narrative review, and level of evidence

supporting the impact of these interventions on prescribing outcomes according to Drekonja et

al. [18]

Interventions targeting healthcare Interventions aiming at modifying the

professionals healthcare system

Description Level of evidence Description Level of evidence

[18] [18]

Education Low Limiting the over-the N/A

counter use of
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Communication Medium antibiotics

skills training

Guidelines Low Unit dispensing of N/A


Clinical decision Low Reducing the number N/A

support systems of available

antibiotics or

increasing the price

of antibiotics

Delayed prescribing Low Separating N/A

prescribing and

dispensing of


Education material Low Prescribers’ N/A

for patients remuneration system

Public commitment N/A Pay-for-performance Low

Point-of-care Medium Public reporting N/A

diagnostic tests

Selective N/A Sickness leave N/A

susceptibility regulation


Quality indicators N/A Limiting advertising N/A

of antibiotics

Audit and feedback Low

Restrictive Low
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prescribing measures

N/A not available